Adenosine is a naturally occurring purine nucleoside, from which is derived a range of agonists at adenosine receptors having considerable potential in the treatment of human disease (Life Sciences, 1991, 49, 1435-1453; Journal of Medicinal Chemistry, 1992, 35,407-422; Annual Reports in Medicinal Chemistry, 1993, 28, 295-304).
Adenosine has been shown to have a number of significant effects on the mammalian central nervous system (CNS) (Annual Reports in Medicinal Chemistry, 1988, 23, 39-48; Adenosine in the Nervous System, T. W. Stone, Ed., Academic Press Ltd., London 1991) especially under conditions of neuronal stress where the compound appears to act as an endogenous neuroprotectant (Progress in Neurobiology, 1988, 31, 85-108, Trends in Pharmacological Sciences, 1992, 11,439-445). For example, the concentration of adenosine has been demonstrated to rise greatly in certain brain regions following epileptic seizures or conditions of neuronal ischaemia/anoxia (Brain Research, 1990, 516, 248-256).
It has been established for some years now that centrally acting adenosine receptor agonists or compounds which increase extracellular adenosine levels can exhibit what is termed neuromodulator activity (Trends in Neurosciences, 1984, 164-168). Such substances influence the release of neurotransmitters in regions of the central nervous system (Annual Review of Neuroscience, 1985, 8, 103-124; Trends in Neurosciences, 1984, 164-168), with particular inhibitory effects on the release of the excitatory amino acid glutamic acid (glutamate) in the CNS (Nature, 1985, 316, 148-150) especially under ischaemic conditions (Journal of Neurochemistry, 1992, 58, 1683-1690).
There are therefore several CNS ailments for which this adenosine receptor mediated neuromodulator activity could be of clear therapeutic benefit. Examples of these would include the treatment of convulsive disorders (European Journal of Pharmacology, 1991, 195, 261-265; Journal of Pharmacology and Experimental Therapeutics, 1982, 220, 70-76; European Journal of Pharmacology, 1993, 242, 221-228), prevention of neurodegeneration under conditions of brain anoxia/ischaemia (Neuroscience Letters, 1987, 83, 287-293; Stroke, 1988, 19, 1133-1139; Neuroscience, 1989, 30, 451-462; Pharmacology of Cerebral Ischaemia 1990, (Kriegelstein, J. and Oberpichler, H., Eds., Wissenschaftliche Verlagsgesellschaft mbH: Stuttgart, 1990, pp 439-448; Trends in Pharmacological Sciences 1992, 11,439-445) or the use of a purinergic agent in the treatment of pain (European Journal of Pharmacology, 1989, 162, 365-369; Neuroscience Letters, 1991, 121, 267-270).
Adenosine receptors represent a subclass (P.sub.1) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. This subclass has been further classified into two distinct receptor types which have become known as A.sub.1 and A.sub.2. Extensive research has been carried out in a quest to identify selective ligands at these sites. Selective ligands exist for A.sub.1 and A.sub.2 adenosine receptors and the structure-activity relationships of the various reference ligands have been reviewed (Biochemical Pharmacology, 1986, 35, 2467-2481; Comprehensive Medicinal Chemistry, Volume 3, (Hansch, C., Sammes, P. G. and Taylor, J. B., Eds., Pergamon Press PLC: 1990, pp 601-642). Among the known adenosine receptor agonists most selective for the A.sub.1 receptor over the A.sub.2 receptor are the examples where the adenine nucleus is substituted with a cycloalkyl group on the amino function, for example N-cyclopentyladenosine (CPA) and N-cyclohexyladenosine (CHA) (Journal of Medicinal Chemistry, 1985, 28, 1383-1384) or 2-chloro-N-cyclopentyladenosine (CCPA) (Naunyn-Schmiedeberg's Arch. Pharmacol. 1988, 337, 687-689).
Various examples of N-heteroarylalkyl substituted A.sub.1 selective adenosine analogues have been reported in the literature. It should be noted that some of these are named as N-6 or N.sup.6 -substituted adenosine derivatives, but this is equivalent to the American Chemical Society suggested nomenclature where compounds substituted on adenosine's 6-amino position are referred to as N-substituted adenosine derivatives.
There is evidence for further subdivision of adenosine receptors into the subtypes A.sub.2a, A.sub.2b (of high and low affinity), A.sub.3 and A.sub.4. The latest status of these subtypes has been reviewed (Journal of Biological Chemistry, 1992, 267, 6451-6454; Drug Development Research, 1993, 28, 207-213; Trends in Pharmacological Sciences 1993, 290-291). The A.sub.3 receptor (Proceedings of the National Academy of Sciences of the USA, 1992, 89, 7432-7436) appears to be responsible for some of the cardiovascular effects of reference ligands (British Journal of Pharmacology, 1993, 109, 3-5).
The synthesis and pharmacological properties of N-thienylalkyl and N-pyridylalkyl adenosine derivatives has been published in the scientific literature (e.g. Nucleosides and Nucleotides, 1992, 11, 1077-1088; Nucleosides and Nucleotides, 1991, 10, 1563-1572; Canadian Journal of Pharmacology, 1986, 333, 313-322). Furthermore, 2-substituted N-piperidinyladenosine derivatives have been described recently (Bioorganic and Medicinal Chemistry Letters, 1993, 3, 2661-2666).
Certain N-imidazolylalkyl and N-indolylalkyl adenosine derivatives have also been described (Life Sciences, 1987, 41, 2295-3202; Justus Liebigs Annalen der Chemie 1976, 4, 745-761; Chemical & Pharmaceutical Bulletin, 1974, 22, 1410-13, Biochemical Pharmacology, 1974, 23, 2883-2889).
Various studies of the 6-amino subregion of adenosines which include N-heteroarylalkyl substituents have been published (Journal of Medicinal Chemistry 1986, 29, 989-996; Naunyn-Schmiedeberg's Archives of Pharmacology, 1986, 333, 313-322; Biochemical Pharmacology, 1986, 35, 2467-2481).
Examples of modified adenosine derivatives containing a range of N-heteroarylalkyl substituents have been claimed in several patents and patent applications. For example EP 0 232 813 A2 includes N-heteroarylcycloalkylmethyl adenosines which are apparently useful as analgesics, antipsychotics, sedatives, antihypertensives and antianginals.
U.S. Pat. No. 4,600,707 discloses N-benzothienyl adenosines and the corresponding N-oxide and Sodioxides as antipsychotics.
In WO 8504882 N-heteroarylethyl adenosines are claimed as cardiac vasodilators. Some similar analogues containing N-heteroarylalkyl adenosine compounds are included in Ger. Offen. DE 2147314, Ger. Offen. DE 2139107, EP 0 423 776 A2, EP 0 423 777 A2, U.S. Pat. No. 4,340,730 and U.S. Pat. No. 1,164,580 without any mention being made of their potential pharmacological effects on the CNS.
PCT-publication WO 9205177 and U.S. Pat. No. 3,901,876 discloses N-substituted adenosine derivatives with hypotensive properties, none of them being further substituted at the purine 2-position.
Utility of adenosine receptor agonists as cerebral neuroprotectants is claimed in the following patents and patent publications: WO 90/05526, EP 0490818A1, U.S. Pat. No. 5,187,162, EP 526866A1, U.S. Pat. No. 5,219,839, WO 93/08206, WO 93/23417 and WO 93/23418.